When we talk about female hormones, we immediately think of estrogen and frequently don’t give much attention to the other major hormone involved in the female reproductive system – progesterone. Progesterone is like the little sister of estrogen. It compliments and does a lot of things in our body similar to estrogen, but can also behave in completely different ways.
In the uterus, for instance, estrogen stimulates growth of the lining cells whereas progesterone inhibits proliferation and acts more as an “organizer” of these cells. The combined activity of these hormones is what generates the monthly menstrual period. In the breast, estrogen primarily stimulates growth of the ducts whereas progesterone plays a role in promoting development of the milk glands.
Most of our progesterone is made in the ovaries, produced by the cells that line our eggs. If a woman becomes pregnant, the placenta starts making large amounts of progesterone, where it plays a major role in preventing miscarriages and supporting a successful pregnancy. For this reason, progesterone sometimes is used as a treatment to prevent premature births.
However, the main therapeutic use of drugs with progesterone activity has been in birth control pills and for menopause treatment. But, before going further, it is important to go into some definitions. Natural progesterone and all of the drugs that behave like progesterone are called progestogens.
The term progesterone should only be used to refer to the substance that is identical to what our body naturally produces. Many years ago scientists discovered a way to convert substances found in yams into progesterone. However, this product could not be administered as a pill because it was not readily absorbed. About 20 years ago, the drug industry produced a pill form that could be absorbed. You may have heard of the drug Prometrium – which was the initial U.S. commercial progesterone product.
Prior to the arrival of Prometrium, the only options were synthetic progesterone-like drugs formulated to be taken orally. The term for these products is progestins and they include drugs such as norethindrone, levonorgestrel, and medroxyprogesterone (Provera). These are the drugs that were initially used for HRT and are still used in most birth control pills.
With respect to menopause treatment, the main reason to use a progestogen has been to prevent uterine cancer. It was discovered many years ago that taking estrogen by itself would cause an ongoing stimulation of the lining of the uterus that not only would cause abnormal bleeding, but could lead to some malignant changes. By taking a progestogen concurrently these problems are averted. Initially the progestogen was given for 10 to 12 days at the end of every month – basically inducing the same changes that occur during a normal menstrual cycle. It has since been discovered that taking a progestogen daily along with an estrogen effectively prevents cancer.
All of the different progestogens have the same effect on the uterus and, until relatively recently, we assumed they all behaved similarly in other parts of the body. We are now learning this is not the case – not all progestogens trigger the same reactions. Because of this, natural progesterone may be the safest choice to use in HRT. Let me explain why.
Just as with estrogen, there are thousands of progesterone receptors in many areas of the body – the uterus, the breasts, the bones, the blood vessels, the brain, and even the skin. Natural progesterone hooks onto these receptors and triggers various actions. Since synthetic progestins are structurally similar to natural progesterone, but not identical, they can hook on to these receptors but can trigger slightly different actions. In addition, they may hook onto other non-progesterone receptors and trigger other unwanted effects. So, while they can produce “good” progesterone-like effects, in some cases they may cause undesirable effects as well. In the breast, for instance, it is believed some progestins actually trigger the production of agents that may promote malignant changes.
This realization has cast confusion on our understanding of the risks of HRT. Since an oral form of progesterone has only recently been widely available, most of the studies on the benefits and risks of hormone replacement therapy involved women taking synthetic progestins. Researchers are now attempting to sort out which progestogens may be responsible for which outcomes, but this is turning out to be a monumental task because there have been so many combinations of HRT used in the various studies. It appears that women taking synthetic progestins may have higher rates of adverse effects compared to women taking natural progesterone. Studies are showing that progesterone appears to have negligible adverse effects on the heart and cholesterol and may even help lower blood pressure. Additionally, it does not appear to increase the risk of blood clots or breast cancer.
Most experts agree that only estrogen, and not a progestogen, be given to menopausal women who have had a hysterectomy. This is because the current rationale is that the main indication for a progestogen is to prevent uterine cancer. Since these women need not worry about this, there is no reason to use an additional drug, which could increase the risk of taking HRT. But as I have noted – it may primarily be the synthetic progestins that cause issues. Many naturopathic physicians have long advocated that all women use progesterone as part of their HRT. Some providers claim progesterone is needed to “balance” estrogen administration. The science behind this is a little shaky, but as we are learning more about progesterone, there may be more to this than we realize. Besides having some beneficial effects on our bone health, progesterone can also contribute to the relief of hot flashes. Scientists are studying its effects on the brain – it appears to have mild sedative effects and may help anxiety and even improve cognition.
There is much more we need to learn about our “other female hormone” and I will keep you updated in future posts. One major issue is determining the optimal dosing regimen and mode of administration. For instance, there is concern that progesterone creams applied to the skin may not be absorbed well. This could increase the risk of uterine cancer. Generic oral progesterone has recently become available and, at this point, may be the optimal progestogen for hormone replacement therapy.
Dear Dr Rice,
Thank you so much for your very valuable book, The Estrogen Question.
I just finished reading it last night, and your book, along with “Estrogen Matters” by Drs Avrum Bluming and Carol Tavris, are probably the most important and life-changing books I will ever read in my lifetime. Thank you for writing it.
I have only one question that is causing me a lot of confusion.
What is the dosage of Prometrium, for daily use? I am a 52 year old, healthy woman who exercises and doesn’ drink or smoke. I am currently on 100mcg Estradot. My GP says I should use 100mg Prometrium daily. My OB/gyne says I should use 200mg Prometrium daily. What is the standard dose?
Not sure if you are able to answer this via email, but I do appreciate your time. And mostly I wanted to thank you for your incredible book!
Candace Jacobs
Hello Candace, thank you so much for your comments. You don’t know how gratifying it is to feel that you may be making a difference in someone’s life. With respect to your question, I cannot specifically give medical advice, but I can relate the following. The dose of the progestogen should roughly match the estrogen dose – the higher the estrogen dose, the higher the progestogen. The reason for this is to make sure there is adequate progestogen to counteract the effects of estrogen on the uterus. The problem is that the studies have used many different forms and doses of both of these hormones and it is hard to pin down the exact formula. Having said that, most of the studies have indicated that a medium dose of micronized progesterone (which would be 100 mg) taken with the medium dose of estrogen (which would be a 50 mcg patch) is sufficient to protect the uterus. Presumably, then, 200 mg progesterone daily would be suggested to go along with a 100 mcg patch. I wish we had more research to help with questions like yours. Right now, many healthcare providers need to use their best judgment, so that is why there may be differing opinions. If there is a concern whether or not the progestogen is doing its job, some healthcare providers order a pelvic ultrasound periodically to make sure there is no evidence of an abnormal build-up inside the uterus. This is certainly something that should be done if a woman on HRT is having any abnormal bleeding. Sandra
Dear Dr Rice,
Thank you very much for taking the time to respond to my question and for explaining the dosing issues about Prometrium; that makes sense to me as to why there is a discrepancy. I will do as my OB/gyne has instructed.
I have recommended your book to my friends and sister. It’s incredibly well-researched, and lays to rest (in my mind!) the risks vs benefits of HRT. I keep it on my bedside table and refer to it regularly, having highlighted it from cover to cover.
I want to reiterate again how important your book is for women and my gratitude to you for writing it. I continue to be dismayed at how little women know about menopause and the easy solution of HRT to helping alleviate much of the misery and long-term health risks associated with it. I hope your book will change more lives for the better, like it has for mine.
Blessings to you.
Candace
Great commentaries above and enjoyed the reading also. I am also confused about the prometrium dosage and have been on 200 mg every 2 months. I have some friends who take this every day of 100 mg but never have any bleeding. If it is taken every two months for the 10-12 days then there is bleeding. So what makes the progesterone useful if there is never any bleeding.?
Hi Pauline, sorry for the delay in responding. This is a terrific question. It has been shown that taking an estrogen concurrently with a progestogen is effective in preventing cancerous and precancerous changes in the lining of the uterus. The progesterone counteracts the estrogen effects at the cellular level. Because the two hormones are given together, the lining never builds up enough to cause a menstrual flow. Many women prefer this route to avoid the bleeding. Taking 100 mg progesterone daily vs. 200 mg. cyclically (12 days per month) are equivalent in their effectiveness in preventing uterine cancer. It has recently been shown that taking 200 mg progesterone every other month may not be quite as effective, but there simply aren’t large studies to know for sure. Thanks for asking! Sandy
Dear Dr Rice
Based in the UK, I am reading your book with great interest as I have recently embarked on taking female hormone treatment by taking Oestrogel (typically 1.5 pumps) and continuous natural progesterone (Utrogestan 100mg capsule). I am 53 and it’s been over a year since my last period. However, I have experienced some unpleasant side effects to the oral progesterone based on soybean lecithin, particularly loose stools and bloating. I am aware that some women apply the same capsule (100mg) vaginally to avoid such side effects, and that in France, this mode of application is actually preferred and is the norm. Here in the UK, this type of progesterone is not available in lower doses of 45-50 mg, as referred to in your book. So, I am considering taking the 100mg vaginally every other day to achieve a similar lower dosage, as it makes sense not taking it daily as it has less distance to travel to reach the uterus. I shall be discussing this option with a female GP next week. Apparently, this method is not officially endorsed by the NHS, but some GPs do give support for it if the oral capsules are clearly not tolerated. I understand that the calming effects of progesterone are not possible when it is taken vaginally but I am unclear about whether the other benefits of it are affected by taking it vaginally, for example, would it still indirectly stimulate some production of the DHEA hormone in the body? I may be also deficient in this hormone as I have the menopausal symptoms of joint discomfort and muscle aches.
I just thought you might be able to help me to decide about whether to try the vaginal application every other day, based on your further research or feedback from other menopausal women since the publication of your book. Hopefully, my query will also benefit other women with a similar intolerance to oral progesterone, and want to know the implications of taking it vaginally as opposed to orally.
i look forward to your response with gratitude and to continue learning more about menopausal hormone replacement. I also wanted to say thank you for writing such a comprehensive book on the subject as it has been a game changer for me here in England to ask for treatment, kind regards, Eira
Hello Eira, I really appreciate that you sent in this comment and thank you for your kind words about my book. You bring up a very interesting issue. Many women simply cannot tolerate progesterone, likely due to genetic differences in the way their bodies react to it. Giving progesterone via the vagina is one option that may help. Studies show that the same dose given vaginally vs. orally leads to lower concentrations in the blood, and thus less side effects. This is because when progesterone is inserted in the vagina, it goes directly to the uterus and the uterus “sucks up” most of it, before it goes into the bloodstream. And, since this leads to high concentrations of progesterone in the uterus, it protects the uterus from cancer. In addition, oral progesterone is converted in the liver into some other derivatives that may cause side effects, whereas these derivatives would be much lower when given vaginally.
On the converse, since lower amounts of progesterone and these derivatives end up in the blood stream, there will be less effects in the brain as well (such as the anti-anxiety and calming effects that some women note with progesterone).
The big question is how much vaginal progesterone is enough. The study I referred to in my book used 45 mg, but this was a progesterone gel, such as Crinone. This product is formulated with a bio-adhesive that makes it “stick” longer in the vagina, so less is “wasted.” A progesterone capsule, like Utrogeston likely may not get fully absorbed, so likely less than 100 mg actually even reaches the uterus. Also, I came across a study that compared 100 mg of Utrogestan (made in France) and 50 mg Yimaxin (another vaginal progesterone tablet made in China that apparently does not have an oil base) that showed that the blood levels obtained from these products was comparable.
Also of note is that different progesterone capsules use different oils. In the U.S. the products use peanut oil.
As far as using 100 mg of vaginal progesterone every other day, an expert panel concluded that this appears to be acceptable and as effective as a daily dose of 45 mg of Crinone gel. (the article that notes this is: Stute P, Neulen J, Wildt L. The impact of micronized progesterone on the endometrium: a systematic review. Climacteric 2016;19:316–28.
If there is uncertainty about how well every other day progesterone in the form you are looking at taking is getting absorbed, one option would be to do a pelvic ultrasound after 6 to 12 months and make sure the lining of the uterus is not building up.
I hope you find this information helpful. Sandra
Hello Eira, I am curious about your experience with the progesterone. I think women in the U.S. would benefit from hearing more about this form of HRT and how women in England, France and the rest of Europe are finding it. Sandra